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Published on: January 3, 2013
Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric
Hans A Schlößer1, Uta Drebber2, Michael Kloth3
1Department of General, Visceral and Cancer Surgery, University of Cologne, Germany; Cologne Interventional Immunology, University of Cologne, Germany; Gastrointestinal Cancer Group Cologne, University of Cologne, Germany.
Abstract:
Remarkable efficacy of immune checkpoint inhibition has been reported for several types of solid tumors and early studies in gastric adenocarcinoma are promising. A detailed knowledge about the natural biology of immune checkpoints in gastric adenocarcinoma is essential for clinical and translational evaluation of these drugs. This study is a comprehensive analysis of cytotoxic T lymphocyte associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) expression in gastric adenocarcinoma. PD-L1 and CTLA-4 were stained on tumor sections of 127 Caucasian patients with gastric adenocarcinoma by immunohistochemistry (IHC) and somatic mutation profiling was performed using targeted next-generation sequencing. Expression of PD-L1 and CTLA-4 on lymphocytes in tumor sections, tumor-draining lymph nodes (TDLN) and peripheral blood were studied by flow-cytometry and immune-fluorescence microscopy in an additional cohort. PD-L1 and CTLA-4 were expressed in 44.9% (57/127) and 86.6% (110/127) of the analyzed gastric adenocarcinoma samples, respectively. Positive tumor cell staining for PD-L1 or CTLA-4 was associated with inferior overall survival. Somatic mutational analysis did not reveal a correlation to expression of PD-L1 or CTLA-4 on tumor cells. Expression of PD-1 (52.2%), PD-L1 (42.2%) and CTLA-4 (1.6%) on tumor infiltrating T cells was significantly elevated compared to peripheral blood. Of note, PD-1 and PD-L1 were expressed far higher by tumor-infiltrating lymphocytes than CTLA-4. In conclusion, specific immune checkpoint-inhibitors should be evaluated in this disease and the combination with molecular targeted therapies might be of benefit. An extensive immune monitoring should accompany these studies to better understand their mode of action in the tumor microenvironment.
Insights
Immune checkpoint proteins programmed death-1 ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are expressed in gastric adenocarcinoma, with higher levels on tumor-infiltrating lymphocytes. Their expression correlates with poorer survival, suggesting potential therapeutic targets.
Area of Science:
- Immunology
- Oncology
- Gastroenterology
Background:
- Immune checkpoint inhibitors (ICIs) show promise in various cancers, including early studies in gastric adenocarcinoma.
- Understanding the natural expression of immune checkpoints like cytotoxic T-lymphocyte-associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) in gastric adenocarcinoma is crucial for ICI therapy evaluation.
Purpose of the Study:
- To comprehensively analyze the expression of CTLA-4 and PD-L1 in gastric adenocarcinoma.
- To investigate the correlation between CTLA-4 and PD-L1 expression and patient survival.
- To compare immune checkpoint expression on tumor-infiltrating lymphocytes versus peripheral blood.
Main Methods:
- Immunohistochemistry (IHC) was used to stain PD-L1 and CTLA-4 on tumor sections from 127 gastric adenocarcinoma patients.
- Somatic mutation profiling was performed using targeted next-generation sequencing.
- Flow cytometry and immune-fluorescence microscopy were employed to study PD-L1 and CTLA-4 expression on lymphocytes in tumor sections, tumor-draining lymph nodes (TDLN), and peripheral blood.
Main Results:
- PD-L1 and CTLA-4 were expressed in 44.9% and 86.6% of gastric adenocarcinoma samples, respectively.
- Positive tumor cell staining for PD-L1 or CTLA-4 was associated with inferior overall survival.
- Tumor-infiltrating T cells showed significantly higher expression of PD-1 (52.2%) and PD-L1 (42.2%) compared to peripheral blood, while CTLA-4 expression was low (1.6%).
Conclusions:
- Gastric adenocarcinoma exhibits expression of PD-L1 and CTLA-4, with elevated levels on tumor-infiltrating lymphocytes.
- ICI therapy warrants evaluation in gastric adenocarcinoma, potentially in combination with molecular targeted therapies.
- Extensive immune monitoring is recommended to elucidate the mode of action of ICIs within the tumor microenvironment.
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